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- Laaksonen, Reijo, et al.
(författare)
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A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle
- 2006
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects.METHODOLOGY: We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg), atorvastatin (40 mg), or placebo.PRINCIPAL FINDINGS: High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05), while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1) in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein.CONCLUSIONS: High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.
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- Lütjohann, Dieter
(författare)
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Cholesterol homeostasis in the brain : importance of 24S-hydroxylation
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Brain cholesterol is characterized by a very low turnover with very little exchange with lipoproteins in the circulation. We have investigated whether side chain-hydroxylated cholesterol species are important for elimination of cholesterol from the brain. About 80% of 24S-hydroxycholesterol (24S-OH-Chol) present in the body is present in the brain. Plasma concentrations of 24S-OH-Chol in the internal jugular vein and the brachial artery in healthy volunteers were consistent with a net flux of this steroid from the brain into the circulation. 24S-OH-Chot is eliminated by the liver and uptake in the liver (about 7 mg/24 h) was similar to the flux from the brain (about 6 mg/24 h). Intravenously injected deuterium-labeled racemic 24-OH-Chol was eliminated from the circulation of two healthy volunteers with half-lives of 10 and 14h, respectively. Results of experiments with rats exposed to 1802 were also consistent with a flux of 24S-OH-Chol from the brain into the circulation. Investigations in rats in vivo using an 1802-inhalation technique and mass isotopomer distribution analysis revealed that cholesterol synthesis in the brain corresponds to about 0.03 % of the pool per hour and that the conversion of cholesterol into 24S-OH-Chol was of similar magnitude. Brain microsomes converted endogenous cholesterol into 24S-OH-Chol at a similar rate when incubated in the presence of NADPH. As judged by the dependence upon NADPH and oxygen, the enzyme is likely to be a species of cytochrome P-450. Infants and children have a 4-5 times higher circulating level of 24S-OH-Chol than adults. Serum concentrations of 24S-OH-Chol increase dramatically during the first months after birth. It is concluded that conversion of cholesterol into 24S-OH-Chol is a quantitatively important mechanism for elimination of cholesterol from the brain. In a pilot study we tested the hypothesis that plasma levels of 24S-OH-Chol could be used as a putative marker for an altered cholesterol homeostasis in the brain of patients with Alzheimer's disease (AD). The concentration of 24S-OH-Chol in AD patients was significantly higher than in healthy controls and in depressed patients, regardless of the Apo E genotype. The results are consistent with a significant role of the 24S-hydroxylase for cholesterol homeostasis in the brain.
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